Process for making esters of diaryl hydroxy acetic acids



United States Patent PROCESS FOR MAKING ESTERS OF DIARYL HYDROXY ACETIC ACIDS Walter G. Farkas and Leo A. Flexser, Upper Montclair, N. J., assignors to Hoffmann-La Roche Inc., Nutley, N. J a corporation of New Jersey No Drawing. Application February 28, 1956 Serial No. 568,187

12 Claims. (Cl. 260-2943) This invention relates to an improved method for the preparation of tertiary nitrogen-containing esters of diaryl hydroxy acetic acids.

' Known methods for producing tertiary nitrogen-containing esters of diaryl hydroxy acetic acids are generally diflicult operations involving heterogeneous systems, requiring long periods of reaction at high temperatures and yielding poor results. The method of the present invention produces such compounds in high yield in a short reaction time and most of the operation may be carried out at room temperature.

It has now been found that the synthesis of such compounds is greatly facilitated by first forming an alkali metal derivative of the lower alkyl ester of the diaryl hydroxy acetic acid and then reacting the preformed metal derivative with a tertiary nitrogen-containing alcohol as hereinafter described. The lower alkyl ester of the diaryl hydroxy acetic acid must be substantially completely converted to its alkali metal derivativepriorto reaction with the tertiary nitrogen-containing alcohol. When the alkali metal derivative of the lower alkyl ester of the diaryl hydroxy acetic acid is preformed as described above, the desired product is formed in homogeneous solution at relatively low temperature in high yield, usually within one hour, while decomposition is minimized. The alkali metal derivative of the lower alkyl ester of the diaryl hydroxy acetic acid is preferably the sodium or potassium derivative, most preferably the sodium derivative.

The process of this invention may be utilized in general for producing compounds represented by the following structural formula: r

wherein R represents a lower alkylene radical, R and R each represents a lower alkyl radical and R and R each represents an aryl radical. it

According to a second preferred embodiment, the

method of this invention produces compounds in which R; and R in Formula 11 above may be. joined with the.

nitrogen atom in a monocyclic,nitrogen-containing heterocyclic radical, attached to R through the nitrogen atom.

A third embodiment constituting the most preferred application of the method of this invention relates to the production of compounds having the structure in Formula II above wherein a quinuclidinyl radical is attached to the oxygen through a nuclear carbon atom, preferably the carbon atom in the 3-position. In this case, R is part of the quinuclidinyl radical.

The lower alkyl groups represented by R R and R in the above formula are straight chain or branched chain aliphatic radicals preferably containing up to and includ ing 4 carbon :atoms.

yl radicals such as lower alkylphenyl, e. g., p-tolyl, lower alkoxyphenyl, e. g. p-anisyl, as well as polynuclear cyclic radicals such as naphthyl, etc. R R and R may represent the same or different radicals in a. given compound and R and R may similarly represent the same or different aryl radicals in a given compound. Compounds produced by the present method are generally known and are used, for example, as spasmolytics.

The reaction producing the compounds described above proceeds according to the following general reaction scheme wherein R R and A have the same significance defined above and R represents, for example, a lower alkyl group:

It is to be observed that by first submitting the ester to a reaction with the alkali metal, a sodio derivative of the ester is formed. In this manner, the ester which is less reactive of the two principal reactants-the ester and the alcohol-is thereby activated.

The alkali metal derivative, e. g. the sodio derivative, of the lower alkyl ester of diaryl hydroxy acetic acids is prepared by reacting the latter with about an equimolar proportion of the metal in an inert solvent. The inert solvents include inert organic hydrocarbon solvents, for example, the C to C aliphatic hydrocarbon fractions available commercially as Skellysolve (Skelly Oil Co., Kansas City, Mo.) and preferably inert aromatic hydrocarbons such as benzene, toluene or xylene. The metallic sodium is reacted with the lower alkyl ester of the -is discontinued and the mixture. is allowed to cool to room temperature. The sodium metal then settles out in a finely dispersed form as a fine sand. The finely dispersed sodium formed in this way reacts rapidly with the diaryl hydroxy acetic acid ester at about room temperature when added thereto and a clear solution generally results.

It is not necessary to isolate the sodio derivative of the lower alkyl ester of the diaryl hydroxy acetic acid;

from the solvent but the solution may be used. per see;

after the substantially complete reaction of thesodimn,

V The aryl groups represented by R; and R include phenyl and nuclearly substituted phen for the reaction with the tertiary nitrogen-containing alcohol. The same solvent may be used for both. reactions consecutively. If desired, however, the sodio derivative may-be isolated by cooling and crystallizing or by evaponation of the solvent. It is essential that the alkali metal be substantially completely reacted with the lower alkyl ester of the diaryl hydroxy acetic acid prior to the introduction of the tertiary nitrogencontaining alcohol. The completion of the reaction of the ester with the alkali metal may generally be determined visually by formation of a clear solution. and the cessation of evidence of reaction such as evolution of a gas or bubbling.

The esterification reaction is carried out in. an inert solvent, preferably those described above for the reaction involving the alkali metal. The esterl'fication reaction is carried out at a temperature within the range of about 75 to about 1.25 '.C. and within a period of about /2 to about 2 hours. The tertiary nitrogen-containing ester may be extracted from the reaction mixture with a dilute inorganic acid, e. g. a'mine'ral acid such as a hydrohalic acid.

Esters suitable as starting materials for the process of this invention include, for example, lower alkyl esters of benzilic acid, p-tolilic acid, p-anisilic acid, phenyl-ptolyl hydroxy acetic acid, dinaphthyl hydroxy acetic acid, naphthyl phenyl hydroxy acetic acid, etc.

Tertiary nitrogen-containing alcohols which may be e'sterified with the foregoing acid radicals include l-azabicycloalkanols, e. g. l-azabicyclo [2.2.2l-3-octanol (commonly referred to as 3-quinuolidinol and a preferred reactant, 1-azabicyclo[2.2.2]-3-methyl-3-octanol, l-azabicyclo [3.2.1l-6-oc-tanol, 1azabicyclo[3.3.1l-4-nonanol,

and 1 azabicyclo[3.3.l] 2 methyl 4 nonanol, dialkyl amino alkanols, preferably di(lower alkyl) amino alkanols, such as fi-diethyl amino ethanol, 'y-di-n-butyl amino propanol, 'y-diethyl amino propanol, N-piperidyl carbinol, etc.

Example 1 1.2 g. of metallic sodium were dispersed by stirring in 50 cc. refluxing dry toluene for 20 minutes. he stirring was then discontinued and the mixture allowed to cool to about 25 C. The sodium metal settled out as fine sand.

An anhydrous solution of g. of methyl benzilate in 50 cc. dry toluene was then added to the stirring sodium dispersion at room temperature. An immediate vigorous reaction resulted as seen by the copious development of hydrogen gas and gradual disappearance of the sodium particles. The reaction mixture was cooled by means of a cold water bath in order to keep the reaction temperature below 30 C. The reaction was completed after stirring for one hour. A clear, practically colorless solution of the sodio derivative of the methyl ester of benzilic acid was obtained.

The solution obtained above was then heated to about 90 C. with stirring, an anhydrous solution of 5.2 g. 3-quinuclidinol in dry toluene was added, and the resulting clear solution was heated to reflux. Distillate was removed until the vapor temperature was over 110 C., the vapor temperature of pure toluene. About 15 minutes were required for this operation. Refluxing was then continued for another 15 to 30 minutes to assure completeness of reaction. The color of the solution was slightly reddish at the end of the reflux time, changing to a very pale yellow upon cooling.

The clear pale yellow solution was cooled to about C. by means of an ice bath and extracted with. 100 cc., then 50 cc., and again 50 cc. of cold normal :hydrochloric acid. The acid extracts were combined and made alkaline by the addition of about 35 cc. of a 15% sodium hydroxide solution. A cooling bath was used during the neutnalization to keep the temperature of the reaction mixture at 20 to C.

Thecold, alkaline mixture which now contained some 25 cc. of ethyl ether.

colorless solid particles was then extracted with 100 cc., then 50 cc., and again 50 cc. of chloroform. The chloroform extracts were combined, dried over sodium sulfate, and evaporated to incipient crystallization of the product. To the cooled slurry (about 50 cc.) were added. 50 cc. of acetone, and the heavy slurry was kept in a refrigerator overnight for complete crystallization.

The pure white product obtained was then filtered off, washed with some acetone, and dried.

The benzilic acid ester of 3-quinuclidinol obtained weighed 1i.15 gm, M. P. l6016l C. sharp (uncorrected). A second crop of crystalline ester was obtained from the mother liquor after evaporation, weighing 0.47

g., and was combined with the previously obtained product. The total yield was 11.62 gm. or 84.26% of theory.

Example 2 0.6 g. of metallic sodium were dispersed tin 30cc. of dry toluene as. described in Example 1.

7.5 g. of anhydrous methyl benzilate in 30 cc. of-

dry toluene were added to the sodium dispersion at room temperature and reacted as described in Example 1.

The clear solution obtained after complete reaction of the sodium was heated to about C., and a dry solution of 2.35 g. of Z-diethylaminoethanol in 30 cc. of

toluene was added. The solution was heated to reflux and some distillate was removed Until the vapor temperature reached 110-111 C. which occurred after a few minutes of reflux. Refluxing was continued for a total of 30 minutes. The clear solution was cooled and extracted with cc. and then 20 cc. of cold normal hydro- .clhloric acid. The combined extracts were brought to a:

pH of about 12.0 by the addition of a 15% sodium hydroxide solution. The temperature was kept below- 30 C. during this neutralization by means of an ice bath. The cold alkaline solution was then extracted with 100 cc., then 50 cc., and again 50 cc. of ethyl ether. The combined ether extracts were dried over sodium sulfate and the ether was evaporated off. To the remaining colorless thick residue were added some ethanolic HCl and acetone. ,B-Diethylaminoethyl benzilate hydrochloride precipitated as pure white crystals. The slurry was kept in the refrigerator overnight. The product was filtered off, washed with some acetone and dried I The weight of product was 4.53 g., M. P. l72-l73 C. (uncorrected). The product was analytically pure. second crop of crystals weighing 1.8 gm. was obtained from the mother liquor after evaporation to a small volume. The total yield obtained was 6.33 gm. or 'approximately 87% of theory.

Example 3 0.6 gm. of metallic sodium was dispersed in 30 cc. of dry toluene as described in Example 1.

7.5 grns. of anhydrous methyl benzilate in 30 cc. of dry toluene were added to the sodium dispersion at room temperature and reacted as described in Example 1.

The clear solution of the sodio derivative of methyl benzilate was heated to about 90 C. and 3.75 gms. of 3-di-n-butylaminopropanol in 30 cc. of dry toluene were added. The solution was heated to reflux and distillate was removed until the vapor temperature reached 111 C. which occurred after 3 minutes reflux. Refluxing was continued for a total of 30 minutes.

The clear almost colorless solution was cooled to about 25 C. and extracted with 50 cc., then 50 cc. and again 25 cc. of cold normal hydrochloric acid. The combined acid extracts were made alkaline by the addition of 15 sodium hydroxide, keeping the temperature below 30 C. during the neutralization by means of an ice bath. The alkaline solution was extracted with 50 cc., 50. cc. and The combined ether extracts were dried over sodium sulfate and the ether removed by distillation. Ethanolic-HCI and ether were added to the thick, colorless residue-and pure white 7-di-n-but'ylarninopropyl benzilate hydrochloride immediately started to crystallize. Crystallization was completed by overnight refrigeration. The product was filtered, washed with some ether and dried. It weighed 5.46 gms. A second crop was obtained from the mother liquor after evaporation weighing 0.5 gm. The total yield obtained was 5.96 gms. or approximately 69% of theory.

Example 4 0.6 gm. of sodium metal was dispersed in 30 cc. of dry toluene as in Example 1.

7.5 g. of anhydrous methyl benzilate in 30 cc. dry toluene were added to the sodium dispersion at room temperature and reacted as described in Example 1.

The clear solution, after completion of the sodium reaction, was heated to about 90 C. and 2.6 grns. of diethylaminopropanol in. 30 cc. of dry toluene were added. The solution was heated to reflux and the first cc. of distillate were removed. Reflux was continued for a total of 30 minutes.

The clear, almost colorless solution was cooled to about 25 C. and extracted with 50 cc., then 50 cc. and again 25 cc. of cold normal hydrochloric acid. The combined acid extracts were made alkaline by the addition of a sodium hydroxide solution, keeping the temperature at C. to C. by means of an ice bath. The alkaline liquor was then extracted with 50 cc., then 50 cc. and again 20 cc. of ethyl ether. The combined ether extracts were dried over sodium sulfate and the ether was removed by evaporation. Ethanolic-HCl was added to the thick residue until a pH of 3.0 was obtained. Upon addition of ether, pure white -diethylaminopropyl benzilate hydrochloride crystallized out. Crystallization was completed by overnight refrigeration. The product was filtered ofi, washed with some ether and dried.

The weight of the pure white crystalline product was 5.98 gins. or a yield of approximately 79.5% of theory. The product was hygroscopic and after one recrystallization from acetone it melted at about 140-145 C. (uncorrected).

We claim:

1. A process for esterifying a,a-diaryl-a-hydroxy acetic acid with an alcohol of a tertiary amine which comprises reacting said alcohol with at least an equivalent proportion of the alkali metal derivative of an alkyl ester of said a,a-diaryl-a-hydroxy acetic acid.

2. A process for esterifying a,a-diaryl-a-hydroxy acetic acid with an alcohol of a tertiary amine which comprises reacting said alcohol with at least an equivalent proportion of the sodio derivative of a lower alkyl ester of said diaryl hydroxy acetic acid.

3. A process as in claim 2 wherein the reaction is effected in an inert solvent at a temperature in the range of about 75 to 125 C.

4. A process as in claim 3 wherein the tertiary nitrogen-containing ester is extracted from the reaction mixture with a dilute inorganic acid.

5. A process which comprises reacting a lower alkyl ester of a,a-diaryl-a-hydroxy acetic acid with about an 6 equivalent proportion of an alkali metal in an inert solvent until the metal has substantially completely reacted with the ester and reacting the thus produced alkali metal derivative of the ester with an alcohol of a tertiary amine.

6. A process which comprises reacting a lower alkyl ester of a,a-diaryl-a-hydroxy acetic acid with about an equivalent proportion of sodium in an inert solvent until the sodium has substantially completely reacted with the ester and reacting the thus produced sodio derivative of the ester with an alcohol of a tertiary amine.

7. A process for the production of a benzilic acid ester of 3-quinuclidinol which comprises reacting said 3- quinuclidinol with about an equivalent proportion of the alkali metal derivative of lower alkyl benzilate.

8. A process for the production of a benzilic acid ester of 3-quinuclidin0l which comprises reacting said alcohol with about an equivalent proportion of the sodio derivative of methyl benzilate.

9. A process which comprises reacting benzilic acid methyl ester with about an equivalent proportion of metallic sodium in an inert solvent and reacting at least an equivalent proportion of the sodio derivative of the benzilic acid methyl ester formed with 3-quinuclidinol.

10. A process which comprises mixing metallic sodium in an inert organic solvent until the sodium is finely dispersed, reacting the finely dispersed sodium with at least an equivalent proportion of methyl benzilate and reacting the sodio derivative of methyl benzilate with 3- quinuclidinol.

11. A process for the production of compounds having the formula wherein A represents a member of the group consisting of di(lower alkyl)aminoalkylene, morpholylalkylene, piperidylalkylene and azabicycloalkyl, and R and R each represents aryl, which comprises reacting an alcohol of a tertiary amine selected from the group consisting of dialkyl amino alkanol, piperidyl carbinol, morpholyl carbinol and azabicycloalkanol, with about an equivalent proportion of the alkali metal derivative of m,u-diaryl-ahydroxy acetic acid alkyl ester.

12. In a process for the production of tertiary-amino alcohol esters of diaryl hydroxy acetic acids by the reaction of an alcohol of a tertiary amine with a diaryl hydroxy acetic acid, the improvement which comprises forming the alkali metal derivative of the diaryl hydroxy acetic acid ester and reacting said alkali metal derivative with said alcohol.

References Cited in the file of this patent UNITED STATES PATENTS 2,387,447 Holirnann Oct. 23, 1945 2,394,770 Hill Feb. 12, 1946 FOREIGN PATENTS 558,653 Great Britain Jan. 14, 1944 

1. A PROCESS FOR ESTERIFYING A,A-DIARYL-A-HYDROXY ACETIC ACID WITH AN ALCOHOL OF A TERTIARY AMINE WHICH COMPRISES REACTING SAID ALCOHOL WITH AT LEAST AN EQUIVALENT PROPORTION OF THE ALKALI METAL DERIVATIVE OF AN ALKYL ESTER OF SAID A,A-DIARYL-A-HYDROXYACETIC ACID.
 7. A PROCESS FOR THE PRODUCTION OF A BENZILIC ACID ESTER OF 3-QUINCLIDINOL WHICH COMPRISES REACTING SAID 3QUINUCLIDINOL WITH ABOUT AN EQUIVALENT PROPORTION OF THE ALKALI METAL DERIVATIVE OF LOWER ALKYL BENZILATE. 